Madiraju, S. R.MurthyPossik, EliteAl-Mulla, FahdNolan, Christopher J.Prentki, Marc2026-10-222026-10-220163-769XORCID:/0000-0002-6964-3819/work/230893128PubMed:40927981WOS:001598563600001https://hdl.handle.net/1885/733816450Glycerol and glycerol-3-phosphate (Gro3P) are key metabolites at the intersection of carbohydrate, lipid, and energy metabolism. Their production and usage are organismal and cell-type specific. Glycerol has unique physicochemical properties enabling it to function as an osmolyte, protein structure stabilizer, and an antimicrobial and antifreeze agent, important to the preservation of many biological functions. Glycerol and Gro3P are implicated in many physiological and disease processes relating to energy metabolism, thermoregulation, hydration, skin health, male fertility, aging, and cancer. Glycerol has countless applications in the food, pharmaceutical, and cosmetics industries. It is used as a sweetener, preservative, thickening agent, humectant, osmolyte, and cryoprotectant. It is widely used in skin and wound care products, laxatives, in cell and tissue preservation, and in medicines for numerous conditions. Here, we review the multiple uses and functions of glycerol and Gro3P and associated transporters, enzymes, and target genes in health, senescence, and disease. We discuss the evidence that glycerol may be present at much higher levels in tissues and cells than in the blood. We bring particular focus to the newly identified glycerol shunt in the direct formation of glycerol independent of lipolysis and as a pathway allowing cells to adapt to various stresses. Relevant to chronic metabolic diseases, cancer and aging, glycerol and Gro3P present important translational implications and thus warrant much more attention.This work was supported by funds from the Canadian Institutes of Health Research (No. 143308 to M.P. and S.R.M.M.) and the Hevolution Foundation (to M.P. and S.R.M.M.), and from the Dasman Diabetes Institute, Kuwait Foundation for the Advancement of Sciences (to M.P., S.R.M.M., and F.A-M.). E.P. was a recipient of a postdoctoral fellowship from Diabetes Canada. Writing of this review was supported by grants from the Canadian Institute of Health Research, the Hevolution Foundation (HF-GRO-23-1199190-42), and the Dasman Diabetes Institute, Kuwait.28enPublisher Copyright: © The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.Energy metabolismGlycerol metabolismGlycerol shuntGlycerol-3-phosphateGlycerolipid cycleGlyceroneogenesis202510.1210/endrev/bnaf033105027307669